Promethazine hydrochloride, or 10H-Phenothiazine-10-ethanamine, N,N, α-trimethyl-, monohydrochloride, (±)-, is derived from a class of compounds known as phenothiazines. This compound has been shown to possess antihistaminic, sedative, antimotion-sickness, antiemetic, and anticholinergic effects. An injectable form of the drug has been indicated for the following conditions: 1) amelioration of allergic reactions to blood or plasma; 2) in anaphylaxis as an adjunct to epinephrine and other standard measures after the acute symptoms have been controlled; 3) for other uncomplicated allergic conditions of the immediate type when oral therapy is impossible or contraindicated; 4) active treatment of motion sickness; 5) preoperative, postoperative, and obstetric (during labor) sedation; 6) prevention and control of nausea and vomiting associated with certain types of anesthesia and surgery; 7) as an adjunct to analgesics for the control of postoperative pain; 8) for sedation and relief of apprehension and to produce light sleep from which the patient can be easily aroused; and 9) intravenously in special surgical situations, such as repeated bronchoscopy, ophthalmic surgery, and poor-risk patients, with reduced amounts of meperidine or other narcotic analgesic as an adjunct to anesthesia and analgesia.
U.S. Pat. Nos. 4,246,894; 4,071,620 and 3,981,398 each describe various injectable formulations of promethazine. The parenteral formulation of promethazine hydrochloride, in most cases, is intended for deep intramuscular injection. In occasional use, it can be given through the route of intravenous (i.v.) injection.
When used intravenously, promethazine hydrochloride is generally given in a concentration not greater than about 25 mg/mL and at a rate which generally should not exceed about 25 mg/min. It is preferable to inject the drug through the tubing of an i.v. infusion set that is known to be functioning satisfactorily. However, some incidents of venous thrombosis at the injection site have been encountered.1 Other clinical case reports involving the use of promethazine HCl have indicated irritation and other serious adverse reactions at the local area of injection, particularly the gangrene at the extremity of the injection site.2,3 Promethazine hydrochloride has also been reported to raise plasma creatine kinase levels after intramuscular injection, which is an indication of muscle irritation.4 
In laboratory studies, it has been found that precipitates form immediately when promethazine hydrochloride solution is mixed with plasma in vitro. Without being bound by any particular theory, it is believed that this precipitate formation could be related to the venous thrombosis found at the injection site, as well as the cause of other local adverse reactions involving promethazine hydrochloride injection.
It is therefore an object of the invention to provide new formulations containing additives that can minimize the potential of generating precipitate, thereby reducing the possibility of forming thrombosis, as well as reducing other adverse drug reactions at the local area of, and/or at the distal region to the injection site involving phenothiazine derivatives such as promethazine hydrochloride. The invention should also provide new methods for reducing undesirable side effects, e.g. precipitate formation, pain of injection, associated with the use of parenterally administered, e.g. intramuscularly-administered, phenothiazine derivatives. The formulations should be storage stable and pharmaceutically acceptable.